SLFN11 captures cancer-immunity interactions associated with platinum sensitivity in high-grade serous ovarian cancer

Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDA), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens  prior platinum-based chemotherapy treatment, we show, for the first time, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 is associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in a SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated, immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation.   In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer-cell-intrinsic functional dispositions associated with sensitivity to DDA treatment. DU145 wild type and two different SLFN11 knockout clones were treated for 0, 6 or 24 hours with 100 nM gemcitabine